Gene therapy: human germline genetic modifications--assessing the scientific, socioethical, and religious issues.

In this article, we will briefly discuss the scientific, socioethical, and religious implications of technologies that facilitate gene transfer, which is the enabling technology of gene therapy. (1) The timeliness of this topic is predicated as a result of rapid breakthroughs in genetic research, which are facilitated by advances in molecular biology and novel reproductive technologies. This progression has advanced our understanding of how we may utilize genetic transfer, or gene therapy, to correct disease.

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Scientific Issues

Gene therapy proposes to correct the phenotype of disorders that are caused by a genetic mutation by transferring copies of the normal gene into the affected individual or by the elimination of a subset of cells via the transfer of therapeutic or suicide gene(s). (1,2) The success of gene therapy depends largely on the efficiency of vehicles, or "vectors," to transfer a particular transgene to diseased tissues and avoid healthy organs, thus limiting toxicity. (1) Currently, there are a variety of vectors available for gene transfers, which are classified as either viral or nonviral vectors. Since an early attempt to correct the adenosine deaminase deficiency form of severe combined immunodeficiency in humans in 1990, (3) there have been 95 approved gene transfer trials worldwide that have been geared toward treating single-gene disorders. (1) Although the number of these trials indicate the utility of gene therapy for the treatment of these single-gene disorders, actually many more trials of gene therapy have been endeavored for cancer and vascular diseases. In addition, gene transfer technologies are currently being exploited for DNA vaccine strategies aimed at fighting infectious diseases. (4) While these aforementioned technologies offer great promise, gene therapy is still in its infancy, and it is not available outside of clinical trials except for one approved product in China. (5)

Yet, gene therapy strategies are constantly evolving, and ranging in applications from terminally ill patients to adults of reproductive age and children with limited life expectancies. Currently, most gene-based applications have been targeted to nonreproductive cells in the body (somatic cells). However, recent advances in animal research have allowed researchers to consider the possibilities of modifying genes that are transmitted to future generations, by modifying eggs or sperm. (6) When this application of gene therapy is applied to human eggs or sperm, the technique is often referred to as human germline genetic modification (HGGM). (7) Although these advances are paramount for the field as a whole, there are still critical safety issues that need to be tested and resolved before such technologies can be applied to humans.

Socioethical Issues

As a result of the scientific advancements surrounding germline genetic modifications in animal models, human germline genetic modifications may become feasible in the future. This raises the question as to whether we should use such a technology and, if so, for what purpose. Early applications for this procedure will vary in their technical feasibility and perceived demand. An example of one possible gene transfer technology would be to treat disorders such as cystic fibrosis (CF). With respect to CF, HGGM is technically feasible because the single-gene mutation has been identified. However, since CF may be preventable with already existing techniques such as preimplantation genetic diagnosis, the perceived need for using HGGM might be low. More radically, some might envision using HGGM to enhance strength or intelligence. This scenario is less technically feasible because the genetics behind these attributes is still unknown. As it relates to "fixing" a genetic defect before an individual is born as opposed to "enhancing" intelligence, views differ greatly. Opinions differ as to which scenarios are ethical and whether it is probable to significantly distinguish between curative and enhancement-based uses of HGGM. (8)

There are also ethical concerns regarding informed consent of HGGM. In general, research involving human subjects requires investigators to obtain informed voluntary consent before starting a human study. It is difficult to determine what information is necessary to give potential parents, since many of the risks/outcomes are unknown. Critics may argue that informed consent is not adequate because HGGM alters individuals who are not conceived or born yet. Parents often give informed consent for their children to have medical treatment. However, parents may have the right to make decisions as it relates to their children, or future children, but many may speculate that parents do not have the right to do so for many generations to come. (9) There are other issues surrounding HGGM, such as whether these procedures will exacerbate existing social inequalities. Some skeptics believe "yes," due to the fact that HGGM is likely to be extremely expensive and truly benefit only those who could afford it.

The need for public awareness of HGGM and other technologies is paramount. Data concerning these techniques are often confined to academic scholars or governmental groups. Recently, these groups have called for public input on the use of such technologies. (10,11) Until now, there has been little information about what Americans know or think of HGGM. (9) Few Americans have had access to accurate information concerning HGGM. Instead, information about HGGM has come from movies and television in the form of sometimes horrific portrayals of irresponsible scientific research or accidental mishaps. (9) Despite the misinformation and false perceptions concerning HGGM, a survey performed in 2004 by the Genetics and Public Policy Center indicates that some Americans are responding positively to the use of HGGM. To determine public perception about HGGM (and other reproductive technologies), the center conducted a broad survey of 4,834 Americans. Their data illustrated high approval ratings for health-related reasons. In general, Americans remain split on their opinions with regard to use of the technology. For example, 57% approved HGGM to avoid fatal childhood diseases, while 19% would approve using the procedure to enhance the possibility of having children with desirable traits. (9)

Religious Issues

Debates such as described above have also had a significant impact on society's religious communities. In general, there is a widely shared perspective in favor of healing and modern medicine among world religious traditions. Most religions favor the use of medicines as a highly valuable human intervention. This support recognizes that medicines often treat diseases by altering nature in some respect. Yet, some religious traditions become uneasy regarding actions that might alter human nature or affect human relationships. This has been the issue concerning most medical advances, including advances such as HGGM. In the 1990s, religious scholars began to comment on somatic cell gene therapy. They generally stated that these approaches are acceptable because they are an extension of basic medicine, which favors healing. Concerns were raised, but these reservations were not uniquely religious or theological. (12) These concerns focused on safety, the involvement of children, or fair access to the therapy. (13) In contrast, genetic alterations that affect genetic inheritance have caused religious leaders to respond cautiously. These discussions bring out various religious questions, such as whether or not society is "playing God" and interrupting life as God has intended. (14)

Some theologians speculate that techniques such as HGGM reduce human dignity. Human dignity is a quality that is difficult to define. Theologians and worldly scholars have debated whether HGGM would threaten human dignity by creating children in a utilitarian way and raises concerns as to whether each person will be afforded the dignity that he or she deserves. (15) In this regard, the President's Council on Bioethics has written: "A child that is designed with certain qualities in mind might be perceived as artificial or more answerable to his or her own parents rather than their own desires, as compared with a child selected for their own characteristics." This council also stated that these types of technologies could turn procreation into a form of manufacture: promoting a new eugenics, where parents and society seek only the "best" children yielding identical generations. (9)

Discussion

The advancements of gene therapy techniques such as germline genetic modification yield great promise. HGGM maybe on the near horizon; therefore, this is the time to continue serious dialogues as it relates to HGGM. Considerable research must be done to assess the long-term safety before such a technique can be available to the general public. To advance awareness/opinions on this technology, there is a need to disseminate factual information to the general public. Discussions concerning the issues related to HGGM would benefit from the opinions of the community as a whole, including patients, families of those affected with genetic diseases, policy makers, and community organizations that focus on civil rights, women's issues, the environment, business and theological concerns. All these groups must come together to educate themselves and consider the benefits and risks of HGGM. (9)

Acknowledgments

This work was supported by a grant from the National Institutes of Health: T32AI07493-11 (Dr. Casey Morrow). The authors would also like to acknowledge Drs. Maaike Everts, Justin Roth, and Reinhard Waehler for their critical reading of this work.

References

1. Wolff JA, Lederberg J. An early history of gene transfer and therapy. Hum Gene Ther 1994;5:469-480

2. Kaplan JM. Adenovirus-based cancer gene therapy. Curr Gene Ther 2005;5:595-605.

3. Blaese RM, Culver KW, Miller AD, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 1995;270:475-480.

4. Genetic and Public Policy Center. Available at: http://www.dnapolicy.org. Accessed October 6, 2005.

5. Garber K. China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst 2006;98:298-300.

6. Denning C, Priddle H. New frontiers in gene targeting and cloning: success, application and challenges in domestic animals and human embryonic stem cells. Reproduction 2003;126:1-11.

7. McCreath KJ, Howcroft J, Campbell KH, et al. Production of gene-targeted sheep by nuclear transfer from cultured somatic cells. Nature 2000;405:1066-1069.

8. Conte RC. Toward a theological construct for the new biology: an analysis of Rahner, Fletcher, and Ramsey. J Contemp Health Law Policy 1995;11:429-455.

9. Baruch S, Huang A, Pritchard D, et al. Human Germline Genetic Modification: Issues and Opinions for Policymakers. Genetics and Public Policy Center, 2006.

10. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Splicing Life, The Social and Ethical Issues of Genetic Engineering Human Beings. Library of Congress, 1982.

11. Chapman AR, Frankel MS. Designing Our Descendants: The Promises and Perils of Genetic Modifications. Baltimore, The Johns Hopkins University Press, 2003.

12. Frankel MS, Chapman AR. Human Inheritable Genetic Modifications: Assessing Scientific, Ethical, Religious, and Policy Issues. Genetic and Public Policy Centers, 2000.

13. Chapman AR. Unprecedented Choices: Religious Ethics at the Frontiers of Science. Minneapolis, Fortress, 1999, pp 67-68.

14. Chapman AR, Frankel MS, Ramsey P, qouted in Cole-Turner R Human Limits: Theological perspective on Germ-Line Modification Designing Our Desendants: The Promises and Perils of Genetic Modification. In: Chapman AR, Frankel MS, editors. Baltimore, The John Hopkins University Press, 2003.

15. Newman SA, Babies by Design. Conference 5 A.D. January 1.

You only love once--but if you work it right, once is enough.
--Joe E. Louis

Qiana L. Matthews, PhD, and David T. Curiel, MD, PhD

From the Division of Human Gene Therapy, Departments of Medicine, Pathology, Surgery, Obstetrics and Gynecology, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL.

Reprint requests to David T. Curiel, MD, PhD, Division of Human Gene Therapy, 901 19th Street South, BMR2-502, Birmingham, AL 35294-2172. Email: [e-mail]